Hematology. American Society of Hematology. Education Program最新文献

Outcomes for infants diagnosed under 1 year of age with KMT2A-rearranged acute lymphoblastic leukemia (ALL) have remained stagnant over the past 20 years. Successive treatment protocols have previously focused on intensification of conventional chemotherapy, but increased treatment-related toxicity and chemoresistance have led to a plateau in survival. We have now entered an era of immunotherapy with integration of agents, such as blinatumomab or chimeric antigen receptor T-cell therapy, into the standard chemotherapy backbone, showing significant promise for improving the dismal outcomes for this disease. There remains much optimism for the future as a wealth of preclinical studies have identified additional novel targeted agents, such as venetoclax or menin inhibitors, ready for incorporation into treatment, providing further ammunition to combat this aggressive disease. In contrast, infants with KMT2A-germline ALL have demonstrated excellent survival outcomes with current therapy, but there remains a high burden of treatment-related morbidity. Greater understanding of the underlying blast genetics for infants with KMT2A-germline ALL and incorporation of immunotherapeutic approaches may enable a reduction in the intensity of chemotherapy while maintaining the excellent outcomes.

Classical Hodgkin lymphoma (cHL) is associated with excellent outcomes with standard frontline chemotherapy or combined modality therapy. However, up to 25% of patients will have relapsed or primary refractory (RR) cHL. Improving the cure rate with frontline treatment, treatment-related complications and late effects, and poor therapy tolerance with high relapse rates in older patients are unmet needs in the initial management of cHL. The introduction of novel therapies, including the CD30-directed antibody drug conjugate brentuximab vedotin and PD-1 blockade (ie, pembrolizumab or nivolumab), has transformed the treatment of RR cHL and has the potential to address these unmet needs in the frontline setting. Incorporation of these potent, targeted immunotherapies into frontline therapy may improve outcomes, may allow for de-escalation of therapy without sacrificing efficacy to reduce treatment complications, and may allow for well-tolerated and targeted escalation of therapy for patients demonstrating an insufficient response. In this article, we provide a case-based approach to the use of novel agents in the frontline treatment of cHL.

With increasing numbers of patients with hematologic malignancies requiring allogeneic hematopoietic cell transplant (HCT), including minority racial and ethnic groups, the limited availability of matched related donors and matched unrelated donors remains a significant obstacle. Hence, the use of alternative donors such as haploidentical and mismatched unrelated donors (MMUDs) is on the rise. Herein, we present case studies to outline a rational and stepwise approach with a focus on the use of MMUD for HCT in patients with hematologic malignancies. We also review novel approaches used to reduce the incidence of severe graft-versus-host disease and improve HCT outcomes in patients undergoing MMUD HCT.

Myelofibrosis (MF) is a clonal hematopoietic stem cell neoplasm characterized by constitutional symptoms, splenomegaly, and risks of marrow failure or leukemic transformation and is universally driven by Jak/STAT pathway activation. Despite sharing this pathogenic feature, MF disease behavior can vary widely. MF can generally be categorized into 2 distinct subgroups based on clinical phenotype: proliferative MF and cytopenic (myelodepletive) MF. Compared to proliferative phenotypes, cytopenic MF is characterized by lower blood counts (specifically anemia and thrombocytopenia), more frequent additional somatic mutations outside the Jak/STAT pathway, and a worse prognosis. Cytopenic MF presents unique therapeutic challenges. The first approved Jak inhibitors, ruxolitinib and fedratinib, can both improve constitutional symptoms and splenomegaly but carry on-target risks of worsening anemia and thrombocytopenia, limiting their use in patients with cytopenic MF. Supportive care measures that aim to improve anemia or thrombocytopenia are often ineffective. Fortunately, new treatment strategies for cytopenic MF are on the horizon. Pacritinib, selective Jak2 inhibitor, was approved in 2022 to treat patients with symptomatic MF and a platelet count lower than 50 × 109/L. Several other Jak inhibitors are in development to extend therapeutic benefits to those with either anemia or thrombocytopenia. While many other novel non-Jak inhibitor therapies are in development for MF, most carry a risk of hematologic toxicities and often exclude patients with baseline thrombocytopenia. As a result, significant unmet needs remain for cytopenic MF. Here, we discuss clinical implications of the cytopenic MF phenotype and present existing and future strategies to tackle this challenging disease.

Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) carried a very poor prognosis prior to the advent of tyrosine kinase inhibitors (TKIs) that block the activity of the BCR-ABL1 oncoprotein. With improvements in TKI efficacy and allogeneic hematopoietic cell transplantation (HCT), survival has improved over the past 3 decades, and the role of chemotherapy and allogeneic HCT is now changing. Better risk stratification, the application of the third-generation TKI ponatinib, and the use of immunotherapy with the CD19-CD3 bifunctional T-cell engaging antibody blinatumomab in place of chemotherapy has made therapy for Ph+ ALL more tolerable and arguably more efficacious, especially for older patients who comprise most patients with Ph+ ALL.

Gastrointestinal (GI) bleeding is an important cause of morbidity and mortality in von Willebrand disease (VWD). It has been noted that GI bleeding caused by angiodysplasia is overrepresented in VWD patients compared to other causes. The bleeding from angiodysplasia is notoriously difficult to treat; recurrences and rebleeds are common. A growing body of basic science evidence demonstrates that von Willebrand factor negatively regulates angiogenesis through multiple pathways. VWD is clinically highly associated with angiodysplasia. The predisposition to angiodysplasia likely accounts for many of the clinical difficulties related to managing GI bleeding in VWD patients. Diagnosis and treatment are challenging with the current tools available, and much further research is needed to further optimize care for these patients with regard to acute treatment, prophylaxis, and adjunctive therapies. In this review we provide an overview of the available literature on GI bleeding in VWD and explore the molecular underpinnings of angiodysplasia-related GI bleeding. Considerations for diagnostic effectiveness are discussed, as well as the natural history and recurrence of these lesions and which therapeutic options are available for acute and prophylactic management.

Targeted therapy is a powerful treatment option in chronic lymphocytic leukemia (CLL) that has outperformed conventional chemoimmunotherapy in most clinical settings. Except for selected young, fit patients with a mutated immunoglobulin heavy chain variable region gene, most patients benefit from targeted therapy with either a continuous BTK inhibitor or 1-year fixed-duration venetoclax-obinutuzumab as first-line treatment of CLL. Treatment selection is driven by patient-, treatment-, and disease-related factors, encompassing patient preference, concomitant medications, comorbidities, safety profile of the regimen, and TP53 aberration. Clinical trials are actively investigating the simultaneous inhibition of Bruton's tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL-2) proteins with or without a CD20 monoclonal antibody, which can achieve deep response in most patients (52%-89% undetectable minimal residual disease in bone marrow).

Richter's syndrome (RS) is an aggressive histologic transformation of chronic lymphocytic leukemia (CLL), most commonly to diffuse large B-cell lymphoma (DLBCL). Outcomes are generally poor, with complete remission (CR) rates of only about 20% and less than 20% long-term survival with chemoimmunotherapy (CIT). RS is biologically heterogeneous, and in 80% of patients with CLL who develop DLBCL, the disease is clonally related to the CLL. Clonally unrelated cases are genetically and immunologically distinct from clonally related DLBCL-RS, have more favorable responses to CIT, and are best treated as de novo DLBCL. Relatively favorable outcomes with CIT are also seen in patients who have never previously received treatment for CLL and who lack TP53 mutation or deletion. For the remaining patients, treatment on a clinical trial is optimal. Fortunately, numerous agents are now in clinical development that show encouraging results. Here we review clinical data for some of the most promising approaches. DLBCL-RS tumor cells frequently express programmed cell death 1 protein (PD-1), and several studies have demonstrated activity for PD-1 inhibitors, especially in combination with ibrutinib. The BCL2 inhibitor venetoclax in combination with R-EPOCH CIT achieved CR in 50% of patients, and a study of venetoclax-R-CHOP is ongoing. The noncovalent Bruton's tyrosine kinase inhibitor pirtobrutinib has achieved responses in approximately two-thirds of heavily pretreated patients and, given its favorable toxicity profile, appears ideally suited to combining with other active agents. Finally, we review available data for bispecific antibodies, antibody-drug conjugates, and chimeric antigen receptor T-cell therapy, which, after revolutionizing the treatment of DLBCL, are now being evaluated in RS.